Objective: The objective of this study is to determine the etiology and risk factors for the development of acute respiratory distress syndrome (ARDS) and also the association between clinical and laboratory parameters and outcome in patients with ARDS. Methodology: This was an observational prospective study conducted in the intensive care units of Narayana Medical College and Hospital, Nellore between November 2015 and May 2016. Patients who fulfilled the AECC definition for ARDS and who were mechanically ventilated for more than a 24 h period were selected for the study. Results: Fifty patients who met the predefined criteria were enrolled for the study. Of these 50 cases, females (52%) were slightly more than the male patients and the most common age group was 31–50 years. ARDS was mostly secondary to infectious causes (92%) and the most common etiology for ARDS in our study was direct cause (52%) followed by indirect cause (48%). Factors associated with poor outcome and high mortality are low PaO2/FiO2 (P value <0.001), high SAPS II score (P value <0.001), high SOFA scores (P value 0.001), high max SOFA scores (P value 0.001), and severe lung injury scores (P value <0.001). High procalcitonin levels and C-reactive protein (CRP) levels less than 226 mg/mL showed more number of nonsurvivors (71.8%). There was significant increase in the mortality among patients who were prescribed inotropic support when compared to those who were not (P <0.001). Of the 50 patients enrolled in the study, 33 patients succumbed to their illness with the mortality of 66%. Conclusion: Direct etiology by pulmonary infection was the most common cause for ARDS. Prognostic determinants like PaO2/FiO2 and clinical scores like SOFA, maxSOFA, SAPS II, and LIS had a statistically significant association with mortality. Laboratory parameters like serum albumin were associated with significant mortality whereas CRP and procalcitonin did not show a statistically significant correlation with mortality. The use of a combination of clinical factors and biological markers is a promising strategy that needs to be prospectively validated.

Acute respiratory distress syndrome occurs in response to a variety of insults and is characterized by the development of non cardiogenic pulmonary edema, impaired gas exchange, and bilateral infiltrates on the chest radiograph. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the major causes of acute respiratory failure that are associated with high mortality and morbidity. An understanding of the basic clinical epidemiology of the disease its incidence, diagnosis, etiologic and prognostic factors, relevant disease subsets, mortality, and long-term outcomes are essential to caring for patients with the disease and for designing studies to evaluate potential therapies. There are very few studies on the pattern of ARDS seen in our country. There are anecdotal reports of ARDS in Indian literature associated with different tropical diseases and with the certain rare metabolic disorders. The exact association of these life-threatening disorders with ARDS is not clearly described in the Indian literature.

ALI is defined as a syndrome of acute and persistent lung inflammation with increased vascular permeability. In 1994, the American-European Consensus Conference on ARDS [Table 1] issued the following definitions that have been widely adopted by clinicians and researchers.[1],[2]

A ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen

(PaO2/FiO2) between 201 and 300 mm Hg, regardless of the level of positive end-expiratory pressure (PEEP)

No clinical evidence for an elevated left atrial pressure. If measured, the pulmonary capillary wedge pressure is 18 mm Hg or less.

The definition of ARDS is the same as ALI except that the hypoxemia is worse

(PaO2/FiO2≤ 200 mm Hg), regardless of the level of PEEP.

Materials and Methods

Study area: Patients who were diagnosed with ARDS in the intensive care units (ICUs) of Narayana Medical College and Hospital between the months of November 2015 and May 2016 were included in the study.

Method of collection of data

This was an observational prospective study conducted in the ICUs of Narayana Medical College and Hospital, Nellore between November 2015 and May 2016. Patients who fulfilled the AECC definition for ARDS and who were mechanically ventilated for more than a 24 h period were selected for the study. A total of 50 patients were enrolled during the study period. A relevant history was noted and a physical examination was performed on enrollment of the patient into the study. Data were recorded on the day of diagnosis of ALI/ARDS and every 24 h thereafter. Baseline clinical data and demographics including age, sex, and preexisting comorbidities were noted. Patients were scored on day 0 of diagnosis of ARDS using the SAPS II system, SOFA score and lung injury score.

Laboratory investigations

Hemogram, renal and liver function tests, serum electrolytes coagulation profile, arterial blood gases, relevant cultures, and serology for an etiological diagnosis were sent. Chest radiographs were ordered on the day of diagnosis and at periodic intervals to look for worsening or improvement. Serum procalcitonin and C reactive protein levels were sent within 48 h of diagnosis of ARDS. A two-dimensional echocardiography was performed when deemed necessary to rule out myocardial dysfunction. Patients were followed up every 24 h to record vital parameters, new onset organ dysfunction, arterial blood gases, and use of inotropes. In the event of more than one value for any parameter in a 24 h period, the most abnormal value was taken into consideration. The patients were followed up till death or discharge from the ICU.

The etiology was defined as the specific clinical disorder associated with ARDS during the first 24 h and classified as either direct or indirect lung injury. The etiology of ARDS was ascertained on the basis of history and physical examination, radiology, biochemical, and microbiological investigations.

Inclusion criteria

Patients that fulfilled the AECC criteria for ARDS

Acute onset of bilateral chest infiltrates on chest radiograph

PaO2/FiO2 < 300 for ALI < 200 for ARDS

Absence of left atrial hypertension or cardiac failure (assessed clinically or echocardiographically)

Patients that were mechanically ventilated > 24 h

Exclusion criteria

Patients were excluded from the study if there was evidence of heart failure either on clinical examination or on echocardiography. Patients under the age of 18 years were also excluded from the study.

Statistical analysis

Statistical analyses were performed using a statistical software package (SPSS for Windows, version 17.0, SPSS Inc, Chicago, IL). Descriptive frequencies were expressed using the mean (SD) and the median (range and interquartile range [IQR]). Differences between the means of categoric variables were compared with the Chi Square test. Levels of significance were expressed as P values (95% confidence intervals [CIs]).

Results

Fifty patients that met the pre defined criteria were enrolled for the study. Of these 50 cases, females (52%) were slightly more than the male patients and the most common age group was 31–50 years [Figure 1] and [Figure 2]. ARDS was mostly secondary to infectious causes (92%) and the most common etiology for ARDS in our study was direct cause (52%) of which pulmonary infection (48%) and aspiration (4%), followed by indirect causes (48%) like sepsis (42%), postsurgery (4%) and severe nonthoracic trauma (2%) [Figure 3], [Figure 4] and [Figure 5]. Patients with comorbidities like diabetes, hypertension, and both existing together showed an increasing trend toward mortality. Patients with diabetes (14%), hypertension (8%), succumbed to death [Table 2]. Fifteen patients (30%) grew organisms on cultures of various body fluids. Two patients were diagnosed with Plasmodium falciparum Malaria on blood smear examination. One patient each were diagnosed with Dengue and Leptospirosis on serology. Factors associated with poor outcome and high mortality are low PaO2/FiO2 (P value <0.001) [Figure 6],high SAPS II score (P value <0.001 ) [Figure 7], high SOFA scores (P value 0.001) [Figure 9], high maxSOFA scores (P value 0.001) [Figure 8] and severe lung injury scores (P value <0.001) [Table 3]. High procalcitonin levels[Table 4] and C-reactive protein (CRP) levels less than 226 mg/mL showed more number of nonsurvivors (71.8%) [Table 5] and [Table 6]. It was noted that the percentage of nonsurvivors was higher in classes with lower albumin [Table 7]. The mean albumin among nonsurvivors was lower than that of nonsurvivors, 2.5 vs 2.8 g/dL(P 0.06). There was significant increase in the mortality among patients who were prescribed inotropic support when compared to those who were not (P < 0.001) [Figure 10]. The outcomes in patients with ARDS secondary to direct and indirect causes showed no significant difference. Patients who developed ARDS secondary to sepsis had better outcome (36%) than those who developed it secondary to other causes (P value 0.012). There was no significant difference in the length of ICU stay and duration of ventilation between the survivors and nonsurvivors [Table 8]. Of the 50 patients enrolled in the study, 33 patients succumbed to their illness with the mortality of 66% [Figure 11].

A total of 50 patients that met the AECC definition of ALI/ARDS were studied. The females compromised slightly more than half the study group at 52%, the rest were males. The mean age of the patients enrolled in our study was 43.26 (17.6) years. There was no statistically significant increase in mortality seen with increasing age in our study although a significant association between age and mortality has been shown in several studies. However, in a study conducted in North India by Agarwal et al.,[3] it was observed that when patients aged more than 50 years were compared to younger patients, the outcome was not significantly different. In a study done by Parmavathi et al.,[4] female population was more affected which is similar to our study. Pulmonary infection (48%) followed closely by sepsis (42%) were the most common causes for ARDS in this study. A study conducted by Vigg et al.[5] in Hyderabad had made similar observations with primary pulmonary infection being the most common cause of ARDS. In 56% of the patients in the study, ARDS could be attributed to direct causes predominantly pulmonary infection. Ninety two percent of the cases of ARDS in this study were secondary to infectious causes. Other studies conducted by Agarwal et al.[3] on 180 patients and Parmavathi et al.[4] concluded that direct pneumonia was the common cause of ARDS which was similar to our study. Another study done by Kenichiro et al.[6] on 173 patients using transpulmonary thermodilution technique yielded results in parallel to our study where 117 patients were affected by direct cause. Our study was in consistent with all these former studies, thus concluding that direct infection is the most common cause of ARDS.

A multivariate analysis to identify early predictors of survival in ARDS by Monchi et al.[7] showed a significant association between mortality and SAPS II score, serum bicarbonate and the prescription of inotropes(P < 0.001). In a study done by Prakash et al.,[8] on usefulness of SAPS II score in 100 ICU patients concluded that SAPS II score reliably predicts that mortality. These study results are similar to our study.

Hemodynamic profile of ARDS was studied by Squara et al.[9] They had concluded that PaO2/FiO2 ratio at admission was an independent predictor of survival. However, an analysis performed by Kraft et al.[10] showed that statistical comparisons of the PaO2/FiO2 ratio of survivors and nonsurvivors were not significant on the first day of ARDS. Our results were consistent with the former study.

A study by Maskara et al.[11] conducted in CMC Vellore showed that lower albumin levels were associated with greater mortality and higher lung injury scores. It was noted that the percentage of nonsurvivors were higher in classes with lower albumin. The mean albumin among nonsurvivors was lower than that of survivors, 2.5 vs 2.8 g/dL (P 0.06). In two other studies done by Hoeboer[12] and Ghazarian[13] also emphasized on the significance of low albumin levels in the outcome of the patients. Our study result was just as similar to the other studies.

A study conducted by Brunkhorst et al.[14] looked into the utility of procalcitonin in discriminating septic from non septic causes of ARDS. They found that procalcitonin levels were significantly higher in those with ARDS secondary to septic causes. Although, it was noted in our study that procalcitonin levels were higher in the subgroup with sepsis induced ARDS (7.6 vs 1.28), the difference did not reach statistical significance (P 0.6).

A study conducted in Taiwan[15] in patients with ARDS secondary to severe community acquired pneumonia (CAP) concluded that PCT analyzed within 72 h of the onset of ARDS predicted mortality. In a study conducted by Tseng et al.,[16] procalcitonin was considered as a valuable prognostic factor in ARDS caused by CAP. The main limitation of the study was its study group number of 22 patients. A trend toward increasing mortality in patients with higher pro calcitonin levels was noted in our study, however, the association was statistically insignificant.

A study performed at the Massachusetts General Hospital by Bajwa et al.[17] studied CRP level and the outcomes in ARDS. They used the Youden method to select an “optimal” CRP level for predicting mortality-the cut-point was found to be 226 mg/dL. They found that among patients with early ARDS, plasma CRP levels were significantly higher among survivors.

In a study conducted by Bajwa et al.,[17] the increasing plasma levels of CRP are associated with improved outcome. In our study the number of nonsurvivors were larger (71.8%) among patients who had CRP values less than 226 mg/mL and were almost equal to the number of survivors among patient with values of CRP more than 226 mg/mL. However, our observation was statistically insignificant (P 0.1).

It was observed that the number of units of blood products transfused were significantly higher in the group of patients that died compared to those that recovered (P 0.03). A study conducted by Gong[18] had noted a similar association. This apparent increase in mortality, among patients transfused larger volumes of blood products, may be either because this group has a greater degree of organ dysfunction thus necessitating transfusions or; may indicate that the transfusions have contributed to the lung injury. To test the latter hypothesis, the correlation between the number of transfusions and the LIS was calculated and was found to be statistically insignificant (P 0.1).

The significance of SOFA score in ARDS was studied by Kao et al.[19] In that study it was concluded that SOFA score predicts the outcome of the patient in ARDS. Another study done by Ferreira et al.[20] on serial evaluation of SOFA in critically ill patients also concluded that SOFA score is a useful predictor in outcome of the patients.

In a multi-institutional study conducted by Morisawa[6] using thermodilution technique found that the SOFA score was significantly higher in ARDS patients especially of indirect etiology. But in a study made by Agarwal on 180 patients of ARDS concluded that the SOFA score is not dependent on the pulmonary or extrapulmonary cause of ARDS. Our present study also concluded that higher SOFA scores were associated with greater mortality (P 0.001). Variables derived from the SOFA score, such as maxSOFA are also considered as outcome predictor.

In a prospective study conducted over 3 years on 170 patients of ARDS concluded low PaO2/FiO2 is associated with increased mortality by Chawla et al.[21] Our study had a similar observation with P 0.001.

In a review published by Krafft et al.[10] of 101 cases of ARDS, the average mortality was 50%, with reported mortality varying from 30 to 70%. A study conducted by Agarwal et al.[22] in a RICU in North India noted a mortality rate of 47.8%. The mortality rate in this study was 66%. There was no difference in mortality between the patients who developed ARDS secondary to direct and those who developed the syndrome as a result of indirect causes. The group of patients who developed ARDS secondary to sepsis had a significantly higher mortality when compared to the group in whom the etiology were factors other than sepsis. These findings corroborate well with a retrospective study conducted at the Post Graduate Institute of Medical Education and Research.[22]

High level of PEEP is applied in patients with ARDS as it opens collapsed alveoli. If this happens throughout the respiratory cycle, cyclic atelectasis is also reduced.[23] In a study conducted by Meade,[23] on 983 patients concluded that there is no difference in the mortality but improved the secondary endpoints related to hypoxemia and use of rescue therapies. In another multicentered randomized control trail done by Mercat et al.,[24] on 767 patients even concluded that the PEEP setting did not improve the outcome but it did improve the lung function and reduced the duration of mechanical ventilation and duration of organ failure. In a meta-analysis conducted by Oba et al.,[25] which included five studies on 2447 patients also concluded significant mortality benefit of high PEEP may exist. In addition, their analysis suggested the effects of high PEEP are greater in patients with higher ICU severity scores. In another study conducted by Rittayamai et al.,[26] they have evidenced the benefits of using high PEEP. In our study high PEEP was associated with good outcome which was consistent with these previous studies (P value <0.001).

In a clinical study conducted by Sharif et al.,[27] multiorgan failure in ARDS with acute renal failure as one of the components with absolute increase in the serum creatinine concentration of ≥0.3 mg/dL from baseline or oliguria of less than 0.5 mL/kg/h for more than 6 h in first 48 h was associated with significant mortality. Our present study is in consistent with this study suggesting that increasing creatinine is associated with high index of mortality (P <0.001).

Thrombocytopenia was associated with the development of ARDS.[28] Enhanced platelet activation resulting in platelet deposition within the damaged pulmonary microvasculature has been supported by several clinical and preclinical studies of ALI. In an international study conducted by Wang et al.,[29] ICU patients in both China and USA showed that thrombocytopenia is associated with an increased risk of ARDS and platelet count in combination with ARDS had a high predictive value for patient mortality. Our study was consistent with this study (P 0.02).

The lung injury score (LIS) remains a commonly utilized measure of lung injury severity though the additive value of LIS to predict ARDS outcomes over the recent Berlin definition of ARDS, which incorporates severity, is not known. In a multi-ICU cohort study conducted by Kangelaris et al.,[30] on 550 ARDS patients concluded the limited value of LIS on predicting the outcome of the patients. Our study showed LIS was significantly high in nonsurvivors which was inconsistent with the previous study.

In our present study the clinical score that had significant association with mortality are LIS, SAPS II, and SOFA. The parameters that had statistically significant association with the mortality are PEEP, PaO2/FiO2, serum bicarbonate, platelet count, serum creatinine, a prescription of inotropes, and number of blood products transfused.

Conclusions

This was a prospective observational study aimed at identifying the distribution of the etiology, the clinical behavior, the factors affecting the course of illness, and the eventual outcome of patients with ARDS among the Indian population.

Pulmonary infections (48%) followed closely by sepsis (42%) were the most common causes for ARDS in this study. Fifty six percent of the cases were attributable to direct causes and 94% of the cases were secondary to infectious etiologies. The PaO2/FiO2 ratio showed a strong correlation with mortality as did the various clinical scores—SOFA, maxSOFA, SAPS II, and LIS. CRP and procalcitonin did not show a statistically significant correlation with mortality but serum albumin did. The mortality in our study was 62% which is comparable to figures reported in literature. A longer duration of study with a larger sample size may be required to consolidate our findings particularly with regard to the utility of CRP and procalcitonin as a prognostic marker in ARDS. The use of a combination of clinical factors and biological markers is a promising strategy that needs to be prospectively validated.

Hoeboer SH, Oudemans-van Straaten HM, Groeneveld ABJ. Albumin rather than C-reactive protein may be valuable in predicting and monitoring the severity and course of acute respiratory distress syndrome in critically ill patients with or at risk for the syndrome after new onset fever, BMC Pulm Med. 2015;15:22.